- New technology has allowed mapping of cells and molecules within the MS brain
- A protein called TREM2 was found on cells involved in clearing damaged tissue, a crucial process that helps enable repair in the brain.
- Insights from human brain bank tissue help guide new ways to repair the brain, especially in progressive MS
Professor Laura Piccio, University of Sydney
When multiple sclerosis (MS) damages the brain and spinal cord, the protective coating around nerves – called myelin – is stripped away. For years, researchers have known that immune cells rush to these damaged areas, but it has been harder to understand what those cells are doing, and why repair often fails, especially in progressive MS.
New MS Australia-funded research, led by Professor Laura Piccio and Dr Claire Goldsbury, with PhD student Yvonne Aguirre-Candia, has taken a closer look at human MS brain tissues from the MS Australia Brain Bank and others, to better understand this process.
Professor Piccio stressed the importance of this resource: “To really advance our understanding of myelin repair and why it fails in MS, we need to carefully map the activity of cells and molecules within affected regions of the brain.”
The team’s findings help explain how the brain tries to clean up damage – and why that clean‑up doesn’t always lead to repair.
TREM2: a key “clean‑up” molecule
The study focused on a protein called TREM2, which sits on the surface of certain immune cells in the brain. These cells, called microglia and macrophages, act like the brain’s clean‑up crew. They remove damaged tissue, including broken‑down myelin.
TREM2 has already been studied in conditions like Alzheimer’s disease, where it helps immune cells deal with fatty debris. This new research shows that TREM2 may also play an important role in MS, particularly in areas where myelin damage is actively happening.
What did the researchers do?
The researchers examined donated brain tissue from people who had MS.
Because this brain bank tissue is so well characterised, the team was able to compare different areas of damage (MS lesions):
- Active lesions, where damage was happening
- Chronic active lesions, which slowly expand over time and are important in disease progression
- Repairing (“remyelinating”) lesions
Professor Piccio (front left), Dr Claire Goldsbury (back row, red) Yvonne Aguirre-Candia (second from front left) and their team at the University of Sydney.
- Normal‑appearing brain tissue
The team examined specific cells within the lesions using routine light microscopy, microscopy with fluorescent “tags” to highlight them.
But as Professor Piccio says, “Newer technologies are transforming how we can interrogate human tissues to uncover a wealth of new insights.
‘Spatial transcriptomics’ allowed us to measure thousands of genes in very precise anatomical regions within MS lesions. This tells us which genes are switched on and off and where, and how different cells are interacting with each other.”
Where is TREM2 found in MS?
The team found that TREM2 was mostly switched on in active and chronic active lesions and was rare in areas that looked normal.
This is important because it shows that TREM2 is closely linked to areas of ongoing damage.
Three types of immune cells, one shared job
In damaged areas, TREM2 was found on three main types of immune cells, called microglia, macrophages and perivascular macrophages.
Although these cells come from different places, they all shared a key feature:
they were filled with fats from broken‑down myelin.
Myelin is very rich in fats, and clearing these away is a necessary first step before repair can begin.
Lipid droplets: storing after cleanup
The team also looked at a marker called PLIN2, which coats tiny fat storage units inside cells. Almost every TREM2‑positive cell also contained PLIN2, showing that these immune cells are actively storing and processing myelin fats.
In contrast, PLIN2‑positive cells were rare in normal brain tissue and abundant only where MS damage was active.
This strongly links TREM2 to fat handling and clean‑up inside MS lesions.
Why clean‑up doesn’t always lead to repair
This might sound like good news, with immune cells working hard to remove damage. But the picture is more complicated.
Within chronic active lesions, areas rich in TREM2 also showed signals that can block the cells responsible for making new myelin. These repair cells, called oligodendrocyte precursor cells, may struggle to move in and mature in this environment.
Although the clean‑up process starts, the conditions created during long‑lasting inflammation which may prevent proper repair.
This may help explain why chronic active lesions, which are common in progressive MS, continue to smoulder rather than heal.
The zone surrounding the lesions matters too
One particularly important finding involved the tissue just outside MS lesions, known as perilesional white matter.
Although this tissue often looks normal on scans, the study showed it contains activated immune cells (microglia), TREM2 activity and early signs of altered fat processing.
This suggests that the area around lesions is not truly healthy and may be involved in lesion growth over time.
What does this mean for people with MS?
This study adds important pieces to our understanding.
Fat metabolism and clean‑up pathways are a central feature during disease progression.
Understanding when immune cells are supporting repair, and when they are preventing it, will be crucial for developing future therapies.
Further research is needed to understand whether the clean‑up role of TREM2 can be supported without blocking repair, and whether these pathways could be targeted to slow MS progression.
This research relies on the profound generosity of individuals who have made the ultimate gift of brain tissue to the MS Australia Brain Bank.
